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CELLS & MECHANISMS OF INNATE IMMUNITY EPITHELIAL CELLS •Pattern recognition receptors (PRR) •Cytokine, chemokine secretion NEUTROPHIL GRANULOCYTES •Phagocytósis •Intracellular cytotoxicity MONOCITE – MACROPHAGE – DENDRITIC CELL NETWORK •Pattern recognition receptors (PRR) •Internalizing receptors •Phagocytosis NATURAL KILLER CELLS •Cytotoxicity •Cytokine production FIRST LINE OF DEFENSE BY INNATE IMMUNITY Soluble proteins – Defensins Enzymes - Complement system - Chemotaxis Recognition by Pattern Recognition Receptors Macrophage & dendritic cell subsets Neutrophils Pro-inflammatory cytokine secretion Local effects Systemic effects Chemokine receptors & ligands – cell recruitment, other functions Cytotoxicity – NK cells CONTACT SURFACES GASTROINTESTINAL SYSTEM Physical, chemical, biological borders EYE AIRWAY SYSTEM Sinuses Trachea Lungs Oral cavity Esophagus Stomach Alimentary tract UROGENITAL SYSTEM SKIN Kidney Bladder Vagina WALDEYER RING Tonsils, adenoids Palatinal, pharyngeal lingual and tubar tonsils Demage Mucus Infection glycoproteins, proteoglycanes, enzymes THE EPITHELIUM AS AN IMPORTANT FIRST LINE OF DEFENSE EPITHELIAL MONOLAYER DEFENSE LINES OF NATURAL IMMUNITY ANATOMICAL BORDERS Skin Inhibits entry of pathogens, pH3 – 5 inhibits growth Mucosa Normal bacterial flora competes for binding sites and nutrients Mucus keeps away pathogens from the surface Cilia remove pathogens PHYSIOLOGICAL BORDERS Temperature Physiological body temperature and fever inhibits growth of certain pathogens Low pH Most pathogens are destroyed in the stomach Chemical Lysosyme degrades bacterial cell wall Type I interferons induce anti-viral resistance The complement system is able to lyse bacteria and promotes phagocytosis PHAGOCYTOSIS/ENDOCYTOSIS Many cells can take up microorganisms by receptor-mediated internalization Special professional phagocytes (monocyte, neutrophil, macrophage) are able to internalize, kill and degrade microorganisms INFLAMMATION Tissue demage and infection results in the leakage of anti-bacterial proteins and peptides to the affected tissue Phagocytic cells leave the blood stream and enter inflammed tissues ORGANIZATION OF IMMUNE CELLS UNDER EPITHELIAL SURFACES Dendritic cell Epithelial cells Stroma cells NK cell NKT cell DC Granulocyte Macrophage PERIFÉRIÁS PERIFÉRIÁS TISSUE – SPECIFIC CELLULAR COMMUNICATION NETWORKS SZÖVETEK LIMFOID SZERVEK PHAGOCYTOSIS, RECOGNITION RECEPTROS, SIGNAL TRANSDUCTION, EFFECTOR MECHANISM Pattern recognition Receptors (PRR) Engagement of PRR triggers phagocytosis and cytokine production Chemoattractant cytokines called chemokines direct migration of leukocytes to the appropriate anatomical sites FAGOCYTE SYSTEM GRANULOCYTES MONOCYTE – MACROPHAGE – DENDRITIC CELL Gatekeeper function Sensing commensals and pathogens Rapid activation of innate immunity Priming adaptive immune responses Maintenance of self tolerance Defence against infectious diseases Elimination of tumor cells Transplantation RECOGNITION BY THE INNATE IMMUNE SYSTEM PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS Toll receptormediated signaling Toll receptor PHAGOCYTES (macrophages, dendritic cells, neutrophil granulocytes) RECOGNIZE PATHOGENS BY PATTERN RECOGNITION RECEPTORS RECOGNITION IS ESSENTIAL Macrophage, dendritic cell – ACT AS TISSUE SENSORS (GATE KEEPERS) Neutrophil granulocytes – MIGRATE FROM THE BLOOD TO THE SITE OF INFLAMMATION INNATE/NATURAL IMMUNITY RECOGNITION Richard Pfeiffer, a student of Robert Koch – ENDOTOXIN There must be a receptor that recognizes endotoxin Lipopolysaccharide (LPS) receptor remained elusive The Dorsoventral Regulatory Gene Cassette Spätzle/Toll/Cactus controls the potent antifungal response in Drosophila adults Bruno Lemaitre, A Hoffmann et al, Cell, 1996 Spätzle: Toll ligand Toll: Receptor Cactus: I-kB Dorsal: NF-kB Drosomycin is not synthesized INNATE (NATURAL) IMMUNITY RECOGNIZING RECEPTORS PROTECTIVE MECHANISMS Enzyme systems Multicellular (Metazoa) Sea urchin 600 million years Toll-receptors C. elegans Drosophila 700 million years IN PLANTS complement TOLL RECEPTORS RECOGNIZE VARIOUS MICROBIAL STRUCTURES Bacteria Virus CpG DNA ssRNS dsRNA Peptidoglycane Gram+ TLR3 IFN TLR7 TLR8 TLR2 Interferon producing cell PC/DC Flagellin LPS Gram- TLR4 TLR6 TLR9 TLR5 Macrophage/Dendritic cell ALL STRUCTURES ARE ESSENTIAL FOR THE SURVIVAL OR REPLICATION OF THE PATHOGEN DANGER SIGNALS ARE TRANSLATED TO CYTOKINE SECRETION THROUGH VARIOUS MOLECULAR SENSORS IN DC SUBTYPES 4 2 1 5 6 6 3 1 7 NLR 7 9 10 8 RLH RLH NLR=NOD/NALP (IL-1β) RLH=RIG-1/MDA5 (IFN) Conventional DC TLR1 – TLR2 – Plasmacytoid DC bacterial lipoprotein (together with TLR2) bacterial lipoprotein, peptidoglycane, lipoteicholic acid IL-1β (heteromer with TLR1 and TLR6) IL-12/23 TLR3 – viral dsRNS, polyI:C IL-10 TLR4 – bacterial LPS TLR5 – bacterial flagellin TLR6 – bacterial lipoprotein (with TLR2) TLR7 – viral ssRNA TLR8 – GU rich viral ssRNS, imidazoquinolin (antiviral drug) TLR9 – unmethylated CpG DNA Th1/Th17/Th2 TLR10 – mdified viral nucleotides IFNαβ NK/DC CONSERVED RECEPTORS/SENSORS THAT DETECT DANGER SIGNALS TLR3 Fibroblast Epithelial cell DC TLR LRR MEMBRANE TIR domain CELL MEMBRANE Bacteria MEMBRANES OF INTRACELLULAR VESICLES vírus TIR: Toll-Interleukin Receptor signaling domain SIGNALING IN INNATE IMMUNITY TOLL RECEPTORS ACTIVATE PHYLOGENETICALLY CONSERVED SIGNAL TRANSDUCTION PATHWAYS Fungus Bacterium Protease LPB LPS Toll Tube Spätzel CD14 Cactus Relish Pelle TLR4 MyD88 CD14 NFkB Drosophila TRIF IRAK IL-1R associated Kinase Peptid TLR3 TLR4 Inflammation Acute phase response Danger signal IL-6 IRF3 STAT1 IFN Macrophage Sensing of LPS by TLR4 leads to activation of the Transcription factor NFkB and the synthesis of inflammatory cytokines. TLR4 activation can lead to the production of either inflammatory cytokines or antiviral type I interferons. TOLL RECEPTOR MEDIATED SIGNALLING NEW THERAPEUTIC TARGET Figure 3 The 'hourglass' shape of the innate immune response. Although microbial stimuli are chemically complex and although the innate immune response ultimately involves the activation of thousands of host genes, innate immune signals traverse a channel of low complexity. Ten Toll-like receptors (TLRs), four TIR (Toll/interleukin-1 receptor homologous region) adaptors and two protein kinases are required for most microbial perception. This circumstance lends itself to effective pharmacotherapeutic intervention. NF-B, nuclear factor-B; STAT1, signal transducer and activator of transcription 1. THE ACUTE PHASE RESPONSE IL- 6 Mannose binding lectin/protein C-reactive protein COMPLEMENT MBL/MBP COMPLEMENT Liver Serum Amyloid Protein (SAP) Mannose/galactose binding Fibrinogen Chromatin, DNA, Influenza IL-6 induces the production of acute phase protiens RECOGNITION BY SOLUBLE MOLECULES MANNOSE BINDING LECTIN PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS MANNOSE RECEPTOR Toll receptor MANNOSE BINDING LECTIN CR3 Toll receptor OTHER PATTERN RECOGNITION MOLECULES GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES Prokariotic cells Eukariotic cells Mannose Glucoseamin Mannose Galactose Sialic acid MANNOSE RECEPTORS ON PHAGOCYTES Mannose Bacterium Mannose Receptor Macrophage/dendritic cells PATTERN RECOGNITION BY MANNAN BINDING LECTIN Bacterium lysis Complement activation LECTIN PATHWAY CR3 Macrophage Phagocytosis Strong binding No binding